rs370097699

chr19-10987789-C-Gchr19-10987789-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001387283.1(SMARCA4):c.983C>G(p.Pro328Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P328L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SMARCA4 NM_001387283.1 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.65

Genes affected

SMARCA4 (HGNC:11100): (SWI/SNF related, matrix associated, actin dependent regulator of chromatin, subfamily a, member 4) The protein encoded by this gene is a member of the SWI/SNF family of proteins and is similar to the brahma protein of Drosophila. Members of this family have helicase and ATPase activities and are thought to regulate transcription of certain genes by altering the chromatin structure around those genes. The encoded protein is part of the large ATP-dependent chromatin remodeling complex SNF/SWI, which is required for transcriptional activation of genes normally repressed by chromatin. In addition, this protein can bind BRCA1, as well as regulate the expression of the tumorigenic protein CD44. Mutations in this gene cause rhabdoid tumor predisposition syndrome type 2. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, May 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, SMARCA4

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SMARCA4	NM_001387283.1	c.983C>G	p.Pro328Arg	missense_variant	6/36	ENST00000646693.2
SMARCA4	NM_003072.5	c.983C>G	p.Pro328Arg	missense_variant	6/35	ENST00000344626.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SMARCA4	ENST00000646693.2	c.983C>G	p.Pro328Arg	missense_variant	6/36		NM_001387283.1
SMARCA4	ENST00000344626.10	c.983C>G	p.Pro328Arg	missense_variant	6/35	1	NM_003072.5	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hereditary cancer-predisposing syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2019

The p.P328R variant (also known as c.983C>G), located in coding exon 5 of the SMARCA4 gene, results from a C to G substitution at nucleotide position 983. The proline at codon 328 is replaced by arginine, an amino acid with dissimilar properties. This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.74
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
Cadd	Uncertain	24
Dann	Uncertain	1.0
DEOGEN2	Uncertain	0.70	D;.;T;.;.;.;.;.;.;.;D;.;.;.;.;.;T;T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Uncertain	0.70	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.25	D
MutationAssessor	Benign	2.0	M;.;.;.;M;M;.;M;M;M;M;M;M;M;M;M;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-2.2	N;.;.;.;.;.;.;.;.;.;N;.;N;.;N;.;N;N
REVEL	Uncertain	0.56
Sift	Benign	0.082	T;.;.;.;.;.;.;.;.;.;T;.;T;.;T;.;T;T
Sift4G	Benign	0.12	T;.;.;.;.;.;.;.;.;.;T;.;T;T;T;T;T;T
Polyphen		0.84	P;.;D;.;.;.;.;.;.;.;P;.;.;.;.;.;.;D
Vest4		0.56
MutPred		0.25		Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);Loss of catalytic residue at P327 (P = 0.0116);
MVP		0.86
MPC		0.87
ClinPred		0.86	D
GERP RS		4.4
Varity_R		0.15
gMVP		0.37

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs370097699; hg19: chr19-11098465;